1. Technical Field
The present invention relates to pharmaceutical compounds. More particularly, the present invention relates to gold(III) complexes having mixed diamine ligands. The present invention includes the use of these gold(III) complexes for treatment of cancers and cell proliferative disorders.
2. Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
The development of new metallodrugs with a pharmacological activity different from platinum drugs is one of the major goals of modern bioinorganic and bio-organometallic medicinal chemistry research [Jankovic S M, Djekovic A, Bugarcic Z D, Jankovic S V, Lukic G, Folic M, Canovic D (2012) Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct. Biometals 25:919-925; Arsenijevic N, Volarevic V, Milovanovic M, Bugarcic Z D (2013) Gold(III) complexes, cytotoxic effects. In: Kretsinger R H, Uversky V N, Permyakov E A (eds) Encyclopedia of metalloproteins, vol 2. Springer, Heidelberg, pp 922-927; Kouroulis K N, Hadjikakou S K, Kourkoumelis N, Kubicki M, Male L, Hursthouse M, Skoulika S, Metsios A K, Tyurin V Y, Dolganov A B, Milaeva E R, Hadjiliadis N (2009) Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides. J Chem Soc Dalton Trans 47:10446-10456; Altaf M, Monim-ul-Mehboob M, Seliman A A, Isab A A, Dhuna V, Bhatia G, Dhuna K (2014) Synthesis, x-ray structures, spectroscopic analysis and anticancer activity of novel gold(I) carbene complexes. J Organomet Chem 765:68-79; Hartinger C G, Dyson P J (2009) Bioorganometallic chemistry—from teaching paradigms to medicinal applications. Chem Soc Rev 38:391-401—each incorporated herein by reference in its entirety]. Among these non-platinum anticancer drugs, gold complexes have recently gained significant attention as a class of compounds with different pharmacodynamic and kinetic properties than cisplatin with strong cell growth inhibiting effects [Kouroulis K N, Hadjikakou S K, Kourkoumelis N, Kubicki M, Male L, Hursthouse M, Skoulika S, Metsios A K, Tyurin V Y, Dolganov A B, Milaeva E R, Hadjiliadis N (2009) Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides. J Chem Soc Dalton Trans 47:10446-10456; Altaf M, Monim-ul-Mehboob M, Seliman A A, Isab A A, Dhuna V, Bhatia G, Dhuna K (2014) Synthesis, x-ray structures, spectroscopic analysis and anticancer activity of novel gold(I) carbene complexes. J Organomet Chem 765:68-79—each incorporated herein by reference in its entirety]. The cell growth inhibiting effects, in many cases, could be related to anti-mitochondrial effects that make the gold complexes interesting [Jankovic S M, Djekovic A, Bugarcic Z D, Jankovic S V, Lukic G, Folic M, Canovic D (2012) Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct. Biometals 25:919-925; Arsenijevic N, Volarevic V, Milovanovic M, Bugarcic Z D (2013) Gold(III) complexes, cytotoxic effects. In: Kretsinger R H, Uversky V N, Permyakov E A (eds) Encyclopedia of metalloproteins, vol 2. Springer, Heidelberg, pp 922-927; Kouroulis K N, Hadjikakou S K, Kourkoumelis N, Kubicki M, Male L, Hursthouse M, Skoulika S, Metsios A K, Tyurin V Y, Dolganov A B, Milaeva E R, Hadjiliadis N (2009) Synthesis, structural characterization and in vitro cytotoxicity of new Au(III) and Au(I) complexes with thioamides. J Chem Soc Dalton Trans 47:10446-10456—each incorporated herein by reference in its entirety].
Oxaliplatin, the so-called third generation of platinum (II) complex was synthesized as the most promising drug molecule in order to overcome the crossresistance experienced by cisplatin [Graham J, Mushin M, Kirkpatrick P (2004) Fresh from thepipeline oxaliplatin. Nat Rev Drug Discov 3(1):11-12—incorporated herein by reference in its entirety]. It bears a 1,2-diaminocyclohexane (1,2-DACH) ligand and oxalate as a leaving group. The bulky chiral ligand, 1R,2R-diaminocyclohexane (1R,2R-DACH), contributes to high cytotoxicity against cisplatin-resistant cell lines. It is possibly due to the steric hindrance effect of the 1,2-DACH-platinum—DNA adducts [Misset J L, Bleiberg H, Sutherland W, Bekradda M, Cvitkovic E (2000) Oxaliplatin clinical activity: a review. Crit Rev Oncol Hematol 35:75-93; Zdraveski Z Z, Mello J A, Farinelli C K, Essigmann J M, Marinus M G (2002) MutS preferentially recognizes cisplatin—over oxaliplatin—modified DNA. J Biol Chem 277:1255-1260—each incorporated herein by reference in its entirety]. In the same line, several substituted 1,2-DACH complexes have been evaluated for their cytotoxicity [Chaney S G (1995) The chemistry and biology of platinum complexes with the 1,2-diaminocyclohexane carrier ligand (review). Int J Oncol 6:1291-1305; Hoeschele J D, Showalter H D, Kraker A J, Elliott W L, Roberts B J, Kampf J W (1994) Synthesis, structural characterization, and antitumor properties of a novel class of large-ring platinum(II) chelate complexes incorporating the cis-1,4-diaminocyclohexane ligand in a unique locked boat conformation. J Med Chem 37:2630-2636—each incorporated herein by reference in its entirety]. Furthermore, a great number of Pt(II) complexes containing 1R,2R-DACH moiety have been synthesized and tested for anticancer activities against a panel of human cancer lines. A few of them have entered preclinical and clinical trials [Yu C W, Li K K, Pang S K, Au-Yeung S C, Ho Y P (2006) Anticancer activity of a series of platinum complexes integrating demethylcantharidin with isomers of 1,2-diaminocyclohexane. Bioorg Med Chem Lett 16:1686-1691; Yu Y, Lou L, Liu W, Zhu H, Ye Q, Chen X, Gao W, Hou S (2008) Synthesis and anticancer activity of lipophilic platinum(II) complexes of 3,5-diisopropylsalicylate. Eur J Med Chem 43:1438-1443—each incorporated herein by reference in its entirety]. Moreover, in search for better platinum(II) compounds, a wide variety of carrying ligands and leaving groups have been screened. Monti E, Gariboldi M, Maiocchi A, Marengo E, Cassino C, Gabano E, Osella D (2005) Cytotoxicity of platinum(ii) conjugate models. The effect of chelating arms and leaving groups on cytotoxicity: a QSAR approach. J Med Chem 48:857-866; Berger I, Nazarov A A, Hartinger C G, Groessl M, Valiandi S M, Jakupec M A, Keppler B K (2007), A glucose derivative as natural alternative to the cyclohexane-1,2-diamine ligand in the anticancer drug oxaliplatin. Chem Med Chem 2:505-514—each incorporated herein by reference in its entirety].
Gold(III) complexes, which are isoelectronic and isostructural to platinum(II) complexes, hold promise as possible anticancer agents [Chaves J D S, Neumann F, Francisco T M, Correa C C, Lopes M T P, Silva H, Fontes A P S, de Almeida M V (2014), Synthesis and cytotoxic activity of gold(I) complexes containing phosphines and 3-benzyl-1,3-thiazolidine-2-thione or 5-phenyl-1,3,4-oxadiazole-2-thione as ligands, Inorg Chim Acta 414:85-90; Cutillas N, Yellol G S, de Haro C, Vicente C, Rodriguez V, Ruiz J (2013), Anticancer cyclometalated complexes of platinum group metals and gold, Coord Chem Rev 257:2784-2797—each incorporated herein by reference in its entirety]. Surprisingly, only a few reports exist in the literature unfolding the cytotoxic properties and the in vivo anticancer effects of gold(III) complexes [van Rijt S H, Sadler P J (2009), Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs, Drug Discov Today 14(23-24):1089-1097; Ronconi L, Marzano C, Zanello P, Corsini M, Miolo G, Macca C, Trevisan A, Fregona D (2006), Gold(III) dithiocarbamate derivatives for the treatment of cancer: solution chemistry, DNA binding, and hemolytic properties. J Med Chem 49:1648-1657—each incorporated herein by reference in its entirety]. Gold(III) complexes having the same square-planar geometries as cisplatin [Zou T, Lum C T, Chui S S, Che C-M (2013) Gold(III) complexes containing N-heterocyclic carbene ligalnds: thiol “Switchon” fluorescent probes and anti-cancer agents. Angew Chem 125:3002-3005; Cattaruzza L, Fregona D, Mongiat M, Ronconi M, Fassina A, Colombatti A, Aldinucci D (2011) Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. Int J Cancer 128(1):206-215—each incorporated herein by reference in its entirety], gold(III) complexes currently became the subject of profound anti-cancer research and hold great potential to enter clinical trials since some of them are highly cytotoxic to solid cancer tumors in vitro and in vivo while causing minimal systemic toxicity [Ronconi L, Aldinucci D, Dou Q P D (2010) Latest insights into the anticancer activity of gold(III)-dithiocarbamato complexes. Anticancer Agents Med Chem 10:283-292; Sun R W Y, Che C M (2009) The anti-cancer properties of gold(III) compounds with dianionic porphyrin and tetradentate ligands. Coord Chem Rev 253:1682-1691—each incorporated herein by reference in its entirety]. In general, gold(III) complexes are not very stable under physiological conditions due to their high reduction potential and fast hydrolysis rate. Therefore, the selection of a suitable ligand to enhance the stability is a challenge in the design of gold(III) complexes. Au(III) is most likely coordinated by at least two chelating nitrogen donors which lower the reduction potential of gold(III) center and by this means stabilize the complex [Giovagnini L, Ronconi L, Aldinucci D, Lorenzon D, Sitran S, Fregoni D J (2005) Synthesis, characterization, and comparative in vitro cytotoxicity studies of platinum(II), palladium(II), and gold(III) methylsarcosinedithiocarbamate complexes. J Med Chem 48:1588-1592; Casini A, Hartinger C, Gabbiani C, Mini E, Dyson P J, Keppler B K, Messori L (2008) Gold(III) compounds as anticancer agents: Relevance of gold—protein interactions for their mechanism of action. J Inorg Biochem 102:564-575—each incorporated herein by reference in its entirety] and facilitated extensive pharmacological investigation, both in vitro and in vivo [Tiekink E R T (2008) Anti-cancer potential of gold complexes. Inflammopharmacology 16:138-142; Casini A, Kelter G, Gabbiani C, Cinellu M A, Minghetti G, Fregona D, Fiebig H H, Messori L (2009) Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study. J Biol Inorg Chem 14:1139-1149—each incorporated herein by reference in its entirety].
1,2-DACH ligand has structurally two asymmetric carbon centers, thus, 1,2-DACH can exist as three isomeric forms which includes two enantiomers (1R,2R-DACH) or (trans-1,2-DACH), (1S,2S-DACH) or (trans-1,2-DACH) and one diastereoisomer (1R,2S-DACH) or (cis-1,2-DACH). Since 1,2-DACH is chiral, the significance of stereochemical issues has been addressed by a number of investigators which affect the cytotoxicity of complexes containing 1,2-DACH [Kidani Y, Inagaki K, Saito R, Tsukagoshi S (1977) Synthesis and anti-tumor activities of platinum(II) complexes of 1,2-diaminocyclohexane isomers and their related derivatives. J Clin Hematol Oncol 7:197-202; Kemp S, Wheate N J, Buck D P, Nikac M, Collins J G, Aldrich-Wright J R (2007), The effect of ancillary ligand chirality and phenanthroline functional group substitution on the cytotoxicity of platinum(II)-based metallointercalators. J Inorg Biochem 101:1049-1058—each incorporated herein by reference in its entirety]. In spite of conflicting views [Gulloti M, Pasini A, Ugo R, Filippeschi S, Marmonti L, Spreafico F (1984) NMR coalescence effects resulting from stereochemical non-rigidity and halide exchange in octahedral rhodium(III) and iridium(III) tertiary phosphine complexes. Inorg Chim Acta 91:223-227; Noji M, Okamoto K, Kidani Y, Tashiro T (1981) Relation of conformation to antitumor activity of platinum(II) complexes of 1,2-cyclohexanediamine and 2-(aminomethyl)cyclohexylamine isomers against leukemia P388. J Med Chem 24:508-515; Pasini A, Velcich A, Mariani A (1982) Absence of diastereoisomeric behaviour in the interaction of chiral platinum anticancer compounds with DNA. Chem Biol Interact 42:311-320—each incorporated herein by reference in its entirety], the consensus is that the (R,R) isomer is generally more active than the (S,S) isomer [Burchenal J H, Kalaher K, O'Toole T, Chisholm J (1977), Lack of cross-resistance between certain platinum coordination compounds in mouse leukemia. Cancer Res 37:3455-3457; Bruck M A, Bau R, Noji M, Inagaki K, Kidani Y (1984), The crystal structures and absolute configurations of the antitumor complexes Pt(oxalato)(1R,2R-cyclohexanediamine) and Pt(malonato)(1R,2R-cyclohexanediamine). Inorg Chim Acta 92:279-284—each incorporated herein by reference in its entirety], although activity has also been demonstrated with the (R,S) isomer [Vollano J F, Al-Baker S, Dabrowiak J C, Schurig J E (1987) Comparative antitumor studies on platinum(II) and platinum(IV) complexes containing 1,2-diaminocyclohexane. J Med Chem 30:716-719—incorporated herein by reference in its entirety]. With regard to the stereochemistry of the complexes, Pt(II)(1R,2R-DACH) and Pt(II)(1S,2S-DACH) complexes have a higher anticancer activity than Pt(1R,2S-DACH) complex [Johnson N P, Butour J L, Villani G, Wimmer F L, Defais M, Pierson V, Brabec V (1989) Metal antitumor compounds: the mechanism of action of platinum complexes. Prog Clin Biochem Med 10:1-24—incorporated herein by reference in its entirety]. However, the analogous gold(III) compound, [Au(en)2]Cl3 has been reported to have higher anticancer activity than gold(III) (1R,2R-DACH) (trans-1,2-DACH) and gold(III) (1S,2S-DACH) (trans-DACH) [Isab A A, Shaikh M N, Monim-ul-Mehboob M, Al-Maythalony B A, Wazeer M I M, Altuwaijri S (2011) Synthesis, characterization and anti proliferative effect of [Au(en)2]Cl3 and [Au(N-propyl-en)2]Cl3 on human cancer cell lines. Spectrochim Acta (A) 79:1196-1201; Monim-ul-Mehboob M, Altaf M, Fettouhi M, Isab A A, Wazeer M I M, Shaikh M N, Altuwaijri S (2013) Synthesis, spectroscopic characterization and anti-cancer properties of new gold(III)-alkanediamine complexes against gastric, prostate and ovarian cancer cells; crystal structure of [Au2(pn)2(Cl)2]Cl2.H2O. Polyhedron 61:225-23; Al-Maythalony B A, Wazeer M I M, Isab A A (2009) Synthesis and characterization of gold(III) complexes with alkyldiamine ligands. Inorg Chim Acta 362:3109-3113; Al-Jaroudi S S, Fettouhi M, Wazeer M I M, Isab A A, Altuwaijri S (2013) Synthesis, characterization and cytotoxicity of new gold(III) complexes with 1,2-diaminocyclohexane: influence of stereochemistry on antitumor activity. Polyhedron 50:434-442; Al-Jaroudi S S, Monim-ul-Mehboob M, Altaf M, Fettouhi M, Wazeer M I M, Isab A A (2014) Synthesis, spectroscopic characterization, X-ray structure and electrochemistry of new bis(1,2-diaminocyclohexane) gold(III) chloride compounds and their anticancer activities against PC3 and SGC7901 cancer cell lines. New J Chem 38:3199-3211—each incorporated herein by reference in its entirety].
As in the case of the parent cisplatin, the anticancer activity of platinum(II)-1,2-DACH is accompanied by toxicity. The emergence of resistance, and low water solubility that can affect pharmacokinetics, are additional features that must be improved in the pursuit for a more effective material [Hanessian S, Wang J (1993) Hydrophilic analogs of (R, R)-diaminocyclohexane dichloroplatinum (DACH) and the influence of relative stereochemistry on antitumor activity. Can J Chem 71:2102-2108—incorporated herein by reference in its entirety]. In view of the foregoing, the present disclosure aims to provide gold(III) complexes having efficacy against a variety of cancers that also lack the severe toxic side effects associated with platinum-based drugs.